A novel ARMC5-containing ubiquitin ligase controls the degradation of HSPA1A and its client protein estrogen receptor alpha

ARMC5 is the substrate recognition subunit of a recently discovered multiple-subunit ubiquitin ligase (ARMC5-E3), which is composed of ARMC5, cullin3, and RBX1. ARMC5-E3 is the major E3 for RNA polymerase II. ARMC5 interacts with multiple heat shock proteins, but the biological significance of these interactions is not known. We discovered that HSPA1A and its client protein, estrogen receptor alpha (ERα), were novel substrates of ARMC5-E3. ARMC5 deletion led to the accumulation of these substrates, while ARMC5 overexpression reduced ERα protein levels. In the presence of estrogen, HSPA1A was no longer bound to ERα, and ARMC5-E3 no longer regulated ERα degradation. Based on transcriptome analysis, ARMC5 overexpression in the presence of estrogen significantly altered the expression of 247 genes in breast cancer MCF7 cells. While estrogen stimulation increased ERE-binding by ERα in MCF7 cells, ARMC5 overexpression reduced it, supporting the notion that ARMC5-E3 degrades ERα and decreases its availability to interact with EREs. In ER-positive human breast cancer patients, increased ARMC5 gene copy number was correlated to longer relapse-free survival time, probably in part due to ARMC5-E3’s effect on reducing HSPA1A-associated ERα levels. Therefore, ARMC5-E3 is a specific E3 that controls the degradation of HSPA1A and ERa. ARMC5 gene copy number variation is associated with tumor-free survival time of breast cancer patients. Hence, ARMC5 is a newly found regulator of estrogen signaling and function, and can serve as a prognostic parameter for breast cancer.